Staphylococcus aureus infections often lead to hematogenous spread that result in inflammation and joint destruction. Although the virulence factors associated with this bacteria have been defined, the role of the host immune response in limiting the inflammatory process is still poorly understood. Using mice with a targeted disruption in IgA gene expression (IgA-/- mice), we have recently shown another yet unrecognized role for IgA. Specifically, IgA appears to serve an essential role in maintenance of overt inflammatory cytokine and nitric oxide (NO) production. We will now investigate in detail the basis for the immunoregulatory role of IgA in modulating systemic inflammatory responses upon bacterial insult. Using a strain of S. aureus that induces sepsis and joint destruction, we will initially examine the precise role of IgA in limiting inflammatory processes using IgA-/- mice. Bacteremia will be assessed in the blood, spleen and kidneys after infection. Inflammatory cytokine production will be monitored in the blood and lymphoid tissues by ELISA and ribonuclease protection analysis respectively. Inflammation in the joints of these animals will be assessed by immunohistochemistry. Since NO production may have both detrimental and beneficial effects during S. aureus infection, we will examine if the absence of IgA potentiates NO expression in the joints of infected mice by histological analyses. Given that the NF-kB pathway is essential in the regulation of iNOS and NO production, we will examine how the absence of IgA affects various components of this pathway by cellular and molecular analyses. Finally we will determine if IgA regulates an inhibitory signaling pathway in macrophages upon bacterial stimulation. Together, these studies will determine if IgA modulates inflammatory responses to systemic bacterial infection by direct interaction with the innate immune system. The results will provide insight on the role of serum IgA to regulate inflammatory processes such as bacterial sepsis and may lead to the use of use of IgA as a therapeutic anti-inflammatory agent.